1. Field of the Invention
The present invention relates to piperazinylalkylpyrazole derivatives, the preparation method thereof and the selective T-type calcium channel blocking activity thereof.
2. Background of the Related Art
Depending on the response to membrane depolarization, calcium channels are classified into two main classes, high voltage activated (HVA) Ca2+ channel and low voltage activated channel (LVA), and particularly, LVA Ca2+ channel is also called as T-type Ca2+ channel. Ca2+ channels exist in neurons, heart, vascular smooth muscle and endocrine cells. The rise of concentration of Ca2+ causes cell death or damage. Therefore, Ca2+ channels are known to be involved in the contractions of atrium and smooth muscle, secretion of cortisol and dI-aldosterone in adrenal cortex, nerve stimulation and tissue development, etc. Inhibition of T-type Ca2+ channel has been reported to have a treatment effect on neuropathic pain, high blood pressure and epilepsy.
Some well-known T-type Ca2+ channel blockers are mibefradil (Ro 40-5967, WO 98/49149), flunarizine (Poauwels, P. J. et al. J. Life. Sci. 1991, 48, 18981), nicardipine (Richard, S. et al. J. Neurosci. Lett. 1991, 132 (2), 229) and a number of derivatives thereof. However, these drugs showed some undesirable side effects due to its pharmacokinetic interactions with other drugs metabolized by cytochromes P-450 3A4 and 2D6. Therefore, they are no longer in use. So it is very likely that the selective T-type channel blockers will be developed as an effective therapeutic agent for illnesses of neuropathic nerve and heart-related diseases, such as pain, epilepsy and high blood pressure.
T-type Ca2+ channel antagonists such as piperazinylalkylisoxazole group (A. N. Pae et al. Bioorganic. Med. Chem. Lett. 2004, 12, 3965-3970) and 3,4-dihydroquinazoline derivatives have been recently reported. (Lee et al. Bioorganic. Med. Chem. Lett. 2004, 14, 3379-3384)
Therefore, an object of the present invention is to provide novel piperazinylalkylpyrazole derivatives or pharmaceutically acceptable salts thereof which have the possibility of being developed into a therapeutic agent for pain, high blood pressure, and epilepsy as a selective T-type Ca2+ channel inhibitor, and the preparation methods thereof.